Phenoxy amine compounds and compositions for delivering active agents

ABSTRACT

Phenoxy amine compounds and compositions for the delivery of active agents are provided. Methods of administration and preparation are provided as well.

This application claims the benefit of U.S. Provisional Application No.60/350,488, filed Nov. 13, 2001, and U.S. Provisional Application No.60/357,288, filed Feb. 15, 2002, both of which are hereby incorporatedby reference.

FIELD OF THE INVENTION

The present invention relates to phenoxy amine compounds for deliveringactive agents, such as biologically or chemically active agents, to atarget. These compounds are well suited for forming non-covalentmixtures with active agents for oral, intracolonic, pulmonary, and otherroutes of administration to animals. Methods for the preparation andadministration of such compositions are also disclosed.

BACKGROUND OF THE INVENTION

Conventional means for delivering active agents are often severelylimited by biological, chemical, and physical barriers. Typically, thesebarriers are imposed by the environment through which delivery occurs,the environment of the target for delivery, and/or the target itself.Biologically and chemically active agents are particularly vulnerable tosuch barriers.

In the delivery to animals of biologically active and chemically activepharmacological and therapeutic agents, barriers are imposed by thebody. Examples of physical barriers are the skin, lipid bi-layers andvarious organ membranes that are relatively impermeable to certainactive agents but must be traversed before reaching a target, such asthe circulatory system. Chemical barriers include, but are not limitedto, pH variations in the gastrointestinal (GI) tract and degradingenzymes.

These barriers are of particular significance in the design of oraldelivery systems. Oral delivery of many biologically or chemicallyactive agents would be the route of choice for administration to animalsif not for biological, chemical, and physical barriers. Among thenumerous agents which are not typically amenable to oral administrationare biologically or chemically active peptides, such as calcitonin andinsulin; polysaccharides, and in particular mucopolysaccharidesincluding, but not limited to, heparin; heparinoids; antibiotics; andother organic substances. These agents may be rapidly renderedineffective or destroyed in the gastro-intestinal tract by acidhydrolysis, enzymes, and the like. In addition, the size and structureof macromolecular drugs may prohibit absorption.

Earlier methods for orally administering vulnerable pharmacologicalagents have relied on the co-administration of adjuvants (e.g.,resorcinols and non-ionic surfactants such as polyoxyethylene oleylether and n-hexadecylpolyethylene ether) to increase artificially thepermeability of the intestinal walls, as well as the co-administrationof enzymatic inhibitors (e.g., pancreatic trypsin inhibitors,diisopropylfluorophosphate (DFF) and trasylol) to inhibit enzymaticdegradation. Liposomes have also been described as drug delivery systemsfor insulin and heparin. However, broad spectrum use of such drugdelivery systems is precluded because: (1) the systems require toxicamounts of adjuvants or inhibitors; (2) suitable low molecular weightcargos, i.e. active agents, are not available; (3) the systems exhibitpoor stability and inadequate shelf life; (4) the systems are difficultto manufacture; (5) the systems fail to protect the active agent(cargo); (6) the systems adversely alter the active agent; or (7) thesystems fail to allow or promote absorption of the active agent.

Proteinoid microspheres have been used to deliver pharmaceuticals. See,for example, U.S. Pat. Nos. 5,401,516; 5,443,841; and Re. 35,862. Inaddition, certain modified amino acids have been used to deliverpharmaceuticals. See, for example, U.S. Pat. Nos. 5,629,020; 5,643,957;5,766,633; 5,776,888; and 5,866,536.

More recently, a polymer has been conjugated to a modified amino acid ora derivative thereof via a linkage group to provide for polymericdelivery agents. The modified polymer may be any polymer, but preferredpolymers include, but are not limited to, polyethylene glycol (PEG), andderivatives thereof. See, for example, International Patent PublicationNo. WO 00/40203.

International Patent Publication Nos. WO 01/32130 and WO 01/32596disclose particular phenyl amine carboxylic acid compounds and phenoxycarboxylic acid compounds for delivering active agents. InternationalPublication No. WO 00/50386 also discloses amine delivery agents.

However, there is still a need for simple, inexpensive delivery systemswhich are easily prepared and which can deliver a broad range of activeagents by various routes.

SUMMARY OF THE INVENTION

The present invention provides compounds and compositions whichfacilitate the delivery of active agents. Delivery agent compounds ofthe present invention include those having the following formula:

or a salt thereofwherein

(a) R¹, R², R³, and R⁴ are independently H, —OH, halogen, C₁-C₄alkyl,C₁-C₄ alkenyl, C₁-C₄alkoxy, —C(O)R⁸, —NO₂, —NR⁹R¹⁰, or —N⁺R⁹R¹⁰R¹¹ (Y⁻);

R⁸ is hydrogen, —OH, C₁-C₆ alkyl, C₁-C₄ alkyl substituted with halogenor —OH, C₂-C₄ alkenyl unsubstituted or substituted with halogen or —OH,or —NR¹⁴R¹⁵;

R⁹, R¹⁰, and R¹¹ are independently hydrogen, oxygen, C₁-C₄ alkylunsubtituted or substituted with halogen or —OH, C₂-C₄ alkenylunsubstituted or substituted with halogen or —OH;

Y is halide, hydroxide, sulfate, nitrate, phosphate, alkoxy,perchlorate, tetrafluoroborate, carboxylate, mesylate, fumerate,malonate, succinate, tartrate, acetate, gluconate, maleate;

R⁵ is H, —OH, —NO₂, halogen, CF₃, —NR¹⁴R¹⁵, —N⁺R¹⁴R¹⁵R¹⁶ (Y⁻), amide,C₁-C₁₂ alkoxy, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, carbamate, carbonate, urea,or —C(O)R²²; R⁵ is optionally substituted with halogen, —OH, —SH, or—COOH; R⁵ is optionally interrupted by O, N, S, or —C(O)—;

R¹⁴, R¹⁵, and R¹⁶ are independently H or C₁-C₁₀ alkyl;

R²² is H, C₁-C₆ alkyl, —OH, —NR¹⁴R¹⁵;

R⁶ is substituted or unsubstituted C₁-C₁₆ alkylene, C₂-C₁₆ alkenylene,C₂-C₁₆ alkynylene, C₅-C₁₆ arylene, (C₁-C₁₆ alkyl) arylene or aryl(C₁-C₁₆alkylene); R⁶ is optionally substituted with C₁-C₇ alkyl or C₁-C₇cycloalkyl;

R⁷ is —NR¹⁸R¹⁹ or —N⁺R¹⁸R¹⁹R²⁰Y⁻;

R¹⁸ and R¹⁹ are independently hydrogen, oxygen, hydroxy, substituted orunsubstituted C₁-C₁₆ alkyl, substituted or unsubstituted C₂-C₁₆ alkenyl,substituted or unsubstituted C₂-C₁₆ alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted alkylcarbonyl (e.g.substituted or unsubstituted (C₁₋₆ alkyl)carbonyl), substituted orunsubstituted arylcarbonyl, substituted or unsubstituted alkanesulfinyl(e.g. substituted or unsubstituted (C₁₋₆ alkane)sulfinyl), substitutedor unsubstituted arylsulfinyl, substituted or unsubstitutedalkanesulfonyl (e.g. substituted or unsubstituted (C₁₋₆alkane)sulfonyl), substituted or unsubstituted arylsulfonyl, substitutedor unsubstituted alkoxycarbonyl (e.g. substituted or unsubstituted (C₁₋₆alkoxy)carbonyl), or substituted or unsubstituted aryloxycarbonyl, orsubstituted or unsubstituted C₅-C₇ heterocyclic ring (i.e., 5, 6, or7-membered heterocyclic ring), wherein the substitutions may be halogenor —OH; and

-   -   R²⁰ is independently hydrogen, substituted or unsubstituted        C₁-C₁₆ alkyl, substituted or unsubstituted C₂-C₁₆ alkenyl,        substituted or unsubstituted C₂-C₁₆ alkynyl, substituted or        unsubstituted aryl, substituted or unsubstituted alkylcarbonyl        (e.g. substituted or unsubstituted (C₁₋₆ alkyl)carbonyl),        substituted or unsubstituted arylcarbonyl, substituted or        unsubstituted alkanesulfinyl (e.g. substituted or unsubstituted        (C₁₋₆ alkane)sulfinyl), substituted or unsubstituted        arylsulfinyl, substituted or unsubstituted alkanesulfonyl (e.g.        substituted or unsubstituted (C₁₋₆ alkane)sulfonyl), substituted        or unsubstituted arylsulfonyl, substituted or unsubstituted        alkoxycarbonyl (e.g. substituted or unsubstituted (C₁₋₆        alkoxy)carbonyl), or substituted or unsubstituted        aryloxycarbonyl; or

(b) R¹-R¹⁶ and R²⁰ are as defined above; and

R¹⁸ and R¹⁹ combine to form a 5, 6, or 7-membered heterocyclic ringoptionally interrupted with an oxo group and unsubstituted orsubstituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, aryl, aryloxy, orcarbocyclic ring.

According to one preferred embodiment, R⁷ is morpholino, morpholiniumsalt, or diethanolamino.

According to another preferred embodiment, R⁶ is a C₁-C₁₆ alkylene andR⁷ is morpholino or a morpholinium salt. Preferably, R⁶ is C₄-C₁₂alkylene, such as an unsubstituted C₄-C₁₂ alkylene. More preferably, R⁶is C₄-C₁₀, C₄-C₈, or C₆-C₈ alkylene, such as an unsubstituted C₄-C₁₀,C₄-C₈, or C₆-C₈ alkylene. According to one embodiment, one of R¹-R⁵ ishydroxy, for example, R¹ can be hydroxy.

According to one embodiment, when R⁶ is a C₁-C₁₀ alkylene, at most oneof R² and R⁴ is halogen. According to another embodiment, R⁶ is aC₈-C₁₆, C₉-C₁₆, C₁₀-C₁₆, or C₁₁-C₁₆ alkylene. For instance, R⁶ may be aC₈, C₉, C₁₀, C₁₁, or C₁₂ alkylene (e.g., a normal C₈-C₁₂ alkylene).According to yet another embodiment, at most one of R¹ and R⁵ is alkyl.

In one preferred embodiment, R¹═—OH and R²═R³═R⁴═R⁵═H or halogen.

In another preferred embodiment, R²═—OH and R¹═R³═R⁴═R⁵═H or halogen.

In another preferred embodiment, R³═—OH and R¹═R²═R⁴═R⁵═H or halogen.

In another preferred embodiment, halogen is F, Cl or Br, more preferablyF or Cl, and more preferably Cl.

In another preferred embodiment, R⁶═C₁-C₁₆ alkylene, (C₁-C₁₆alkyl)arylene or aryl(C₁-C₁₆ alkylene). More preferably R⁶ is C₁-C₁₂alkylene, more preferably C₃-C₁₀ alkylene, more preferably C₄-C₁₀ orC₄-C₈ alkylene, and more preferably C₆-C₈ alkylene. More preferably, R⁶is unsubstituted.

In another preferred embodiment, R⁷═—NR¹⁸R¹⁹ and R¹⁸ and R¹⁹ areindependently C₁-C₄ alkyl (e.g., methyl, ethyl, propyl, or butyl)substituted with —OH. In another preferred embodiment, R⁷═—NR¹⁸R¹⁹ andR¹⁸ and R¹⁹ combine to form a six membered heterocyclic ring substitutedwith an oxo group.

According to one preferred embodiment, R¹ is hydrogen; R², R³, and R⁴are independently hydrogen, halogen, —OH, or —OCH₃; R⁵ is hydrogen, —OH,or —C(O)CH₃; R⁶ is C₁-C₁₂ alkylene, and R⁷ is NR¹⁸R¹⁹ wherein R¹⁸ andR¹⁹ combine to form a 5, 6, or 7 membered heterocyclic ring.

According to another preferred embodiment, one of R³, R⁴, and R⁵ ishydroxy and the others are independently halogen or hydrogen; R¹ and R²are independently halogen or hydrogen; R⁶ is C₁-C₁₆ alkylene; and R⁷ isNR¹⁸R¹⁹ wherein R¹⁸ and R¹⁹ combine to form a 5, 6, or 7 memberedheterocyclic ring. R⁶ is preferably C₆-C₁₆, C₆-C₁₀, C₈-C₁₆, C₁₀-C₁₆, orC₄-C₈ alkylene, such as unsubstituted C₆-C₁₆, C₆-C₁₀, C₈-C₁₆, C₁₀-C₁₆,or C₄-C₈ alkylene. Preferably, R¹⁸ and R¹⁹ form a morpholino orimidazole.

In another preferred embodiment, R¹ is hydrogen; R², R³, and R⁴ areindependently hydrogen, halogen, —OH, or —OCH₃; R⁵ is hydrogen, —OH, or—C(O)CH₃; R⁶ is C₁-C₁₂ alkylene; and R⁷ is N⁺R¹⁸R¹⁹R²⁰ (Y⁻) wherein R¹⁸and R¹⁹ are hydroxy substituted C₁-C₁₆ alkyl and R²⁰ is H.

In another preferred embodiment, R¹ is hydrogen; R², R³, and R⁴ areindependently hydrogen, halogen, —OH, or —OCH₃; R⁵ is hydrogen, —OH, or—C(O)CH₃; R⁶ is C₁-C₁₂ alkylene; and R⁷ is N⁺R¹⁸R¹⁹R²⁰ (Y⁻) wherein R¹⁸and R¹⁹ are hydroxy substituted C₁-C₁₆ alkyl and R²⁰ is H.

In another preferred embodiment, R¹, R², R⁴, R⁵ are independentlyhalogen or hydrogen; R³ is —OH, or —OCH₃; and R⁷ is N⁺R¹⁸R¹⁹R²⁰ (Y⁻)wherein R¹⁸ and R¹⁹ are hydroxy substituted C₁-C₁₆ alkyl and R²⁰ is H.

According to one preferred embodiment, R¹ is hydrogen; R², R³, and R⁴are independently hydrogen, halogen, —OH, or —OCH₃; R⁵ is hydrogen, —OH,or —C(O)CH₃; R⁶ is C₁-C₆ alkylene or aryl substituted C₁-C₁₂ alkyl; andR⁷ is —NR¹⁸R¹⁹ wherein R¹⁸ and R¹⁹ combine to form a 5, 6, or 7 memberedheterocyclic ring or N⁺R¹⁸R¹⁹R²⁰ (Y⁻) wherein R¹⁸ and R¹⁹ are hydroxysubstituted C₁-C₁₆ alkyl and R²⁰ is H.

In another preferred embodiment, the citrate salt of the compound isused.

Preferred delivery agent compounds include, but are not limited to thosehaving the following formulae and salts thereof:

A preferred compound is the mesylate salt of compound 1.

Mixtures of these delivery agent compounds may also be used. Morpholinedelivery agents of the present invention may be converted tomorpholinium salts, which are also delivery agents, by methods known inthe art.

The invention also provides a composition comprising at least one of thedelivery agent compounds of the formulas above, and at least one activeagent. These compositions deliver active agents to selected biologicalsystems in increased or improved bioavailability of the active agentcompared to administration of the active agent without the deliveryagent compound.

Also provided are dosage unit forms comprising the compositions. Thedosage unit may be in the form of a liquid or a solid, such as a tablet,capsule or particle, including a powder or sachet.

Another embodiment is a method for administering an active agent to ananimal, particularly an animal in need of the active agent, byadministering a composition comprising at least one of the deliveryagent compounds of the formulas above and the active agent to theanimal. Preferred routes of administration include the oral andintracolonic routes.

Yet another embodiment is a method of treating a disease or forachieving a desired physiological effect in an animal by administeringthe composition of the present invention.

Yet another embodiment is a method of preparing a composition of thepresent invention by mixing at least one delivery agent compound of theformulas above, and at least one active agent.

DETAILED DESCRIPTION OF THE INVENTION

Delivery Agent Compounds

The terms “alkyl”, “alkenyl”, and “alkynyl” as used herein includelinear and branched alkyl, alkenyl, and alkynyl substituents,respectively.

The delivery agent compounds may be in the form of the free base orsalts thereof. Suitable salts include, but are not limited to, organicand inorganic salts, for example ammonium, acetate salt, citrate salt,halide (preferably hydrochloride), hydroxide, sulfate, nitrate,phosphate, alkoxy, perchlorate, tetrafluoroborate, carboxylate,mesylate, fumerate, malonate, succinate, tartrate, acetate, gluconate,and maleate. Preferred salts include, but are not limited to, citrateand mesylate salts. The salts may also be solvates, including ethanolsolvates, and hydrates.

Salts of the delivery agent compounds of the present invention may beprepared by methods known in the art. For example, citrate salts andmesylate salts may be prepared in ethanol, toluene and citric acid.

In general, the amine compounds of the present invention, i.e. where R⁷is —NR¹⁸R¹⁹, may be prepared by reacting the appropriate phenyl witheither (1) the appropriate dihalogenated alkyl chain or (2) theappropriate haloalkylalcohol which can then be transformed into anappropriate leaving group, such as a methane sulfonic ester (e.g., byreaction with methanesulfonyl chloride), creating an ether compound withan active leaving group that is subsequently reacted with theappropriate amine optionally in the presence of a base, such astriethylamine. To obtain the corresponding salt the amine compound isreacted with the appropriate acid, i.e. to make the citric acid salt,the amine is reacted with citric acid and preferably with an excess ofcitric acid. To obtain the corresponding quaternary ammonium salt whereR⁷ is —NR¹⁸R¹⁹R²⁰ (where R¹⁸, R¹⁹, R²⁰ are not hydrogen), the aminemoiety of the amine compound is alkylated by methods known in the art.

The delivery agent compound may be purified by recrystallization or byfractionation on one or more solid chromatographic supports, alone orlinked in tandem. Suitable recrystallization solvent systems include,but are not limited to, ethanol, water, heptane, ethyl acetate,acetonitrile, acetone, methanol, and tetrahydrofuran (THF) and mixturesthereof. Fractionation may be performed on a suitable chromatographicsupport such as alumina, using methanol/n-propanol mixtures as themobile phase; reverse phase chromatography using trifluoroaceticacid/acetonitrile mixtures as the mobile phase; and ion exchangechromatography using water or an appropriate buffer as the mobile phase.When anion exchange chromatography is performed, preferably a 0-500 mMsodium chloride gradient is employed.

The delivery agent may contain a polymer conjugated to it by a linkagegroup selected from the group consisting of —NHC(O)NH—, —C(O)NH—,—NHC(O), —OOC—, —COO—, —NHC(O)O—, —OC(O)NH—, —CH₂NH—NHCH₂—,—CH₂NHC(O)O—, —OC(O)NHCH₂—, —CH₂NHCOCH₂O—, —OCH₂C(O)NHCH₂—,—NHC(O)CH₂O—, —OCH₂C(O)NH—, —NH—, —O—, and carbon-carbon bond, with theproviso that the polymeric delivery agent is not a polypeptide orpolyamino acid. The polymer may be any polymer including, but notlimited to, alternating copolymers, block copolymers and randomcopolymers, which are safe for use in mammals. Preferred polymersinclude, but are not limited to, polyethylene; polyacrylates;polymethacrylates; poly(oxyethylene); poly(propylene); polypropyleneglycol; polyethylene glycol (PEG); and derivatives thereof andcombinations thereof. The molecular weight of the polymer typicallyranges from about 100 to about 200,000 daltons. The molecular weight ofthe polymer preferably ranges from about 200 to about 10,000 daltons. Inone embodiment, the molecular weight of the polymer ranges from about200 to about 600 daltons and more preferably ranges from about 300 toabout 550 daltons.

Active Agents

Active agents suitable for use in the present invention includebiologically active agents and chemically active agents, including, butnot limited to, pesticides, pharmacological agents, and therapeuticagents. Suitable active agents include those that are rendered lesseffective, ineffective or are destroyed in the gastro-intestinal tractby acid hydrolysis, enzymes and the like. Also included as suitableactive agents are those macromolecular agents whose physiochemicalcharacteristics, such as, size, structure or charge, prohibit or impedeabsorption when dosed orally.

For example, biologically or chemically active agents suitable for usein the present invention include, but are not limited to, proteins;polypeptides; peptides; hormones; polysaccharides, and particularlymixtures of muco-polysaccharides; carbohydrates; lipids; small polarorganic molecules (i.e. polar organic molecules having a molecularweight of 500 daltons or less); other organic compounds; andparticularly compounds which by themselves do not pass (or which passonly a fraction of the administered dose) through the gastro-intestinalmucosa and/or are susceptible to chemical cleavage by acids and enzymesin the gastro-intestinal tract; or any combination thereof.

Further examples include, but are not limited to, the following,including synthetic, natural or recombinant sources thereof: growthhormones, including human growth hormones (hGH), recombinant humangrowth hormones (rhGH), bovine growth hormones, and porcine growthhormones; growth hormone releasing hormones; growth hormone releasingfactor, interferons, including α (e.g., interferon alfacon-1 (availableas Infergen® from InterMune, Inc. of Brisbane, Calif.)), β and γ;interleukin-1; interleukin-2; insulin, including porcine, bovine, human,and human recombinant, optionally having counter ions including zinc,sodium, calcium and ammonium; insulin-like growth factor, includingIGF-1; heparin, including unfractionated heparin, heparinoids,dermatans, chondroitins, low molecular weight heparin, very lowmolecular weight heparin and ultra low molecular weight heparin;calcitonin, including salmon, eel, porcine and human; erythropoietin;atrial naturetic factor; antigens; monoclonal antibodies; somatostatin;protease inhibitors; adrenocorticotropin, gonadotropin releasinghormone; oxytocin; leutinizing-hormone-releasing-hormone; folliclestimulating hormone; glucocerebrosidase; thrombopoietin; filgrastim;prostaglandins; cyclosporin; vasopressin; cromolyn sodium (sodium ordisodium chromoglycate); vancomycin; desferrioxamine (DFO);bisphosphonates, including alendronate, tiludronate, etidronate,clodronate, pamidronate, olpadronate, and incadronate; parathyroidhormone (PTH), including its fragments; anti-migraine agents such asBIBN-4096BS and other calcitonin gene-related proteins antagonists;glucagon-like peptide 1 (GLP-1); antimicrobials, including antibiotics,anti-bacterials and anti-fungal agents; vitamins; analogs, fragments,mimetics or polyethylene glycol (PEG)-modified derivatives of thesecompounds; or any combination thereof. Non-limiting examples ofantibiotics include gram-positive acting, bacteriocidal, lipopeptidaland cyclic peptidal antibiotics, such as daptomycin and analogs thereof.

Delivery Systems

The composition of the present invention comprises one or more deliveryagent compounds of the present invention, and one or more active agents.In one embodiment, one or more of the delivery agent compounds, or saltsof these compounds, or poly amino acids or peptides of which thesecompounds or salts form one or more of the units thereof, may be used asa delivery agent by mixing with the active agent prior to administrationto form an administration composition.

The administration compositions may be in the form of a liquid. Thesolution medium may be water (for example, for salmon calcitonin,parathyroid hormone, and erythropoietin), 25% aqueous propylene glycol(for example, for heparin) and phosphate buffer (for example, for rhGH).Other dosing vehicles include polyethylene glycol. Dosing solutions maybe prepared by mixing a solution of the delivery agent compound with asolution of the active agent, just prior to administration. Alternately,a solution of the delivery agent compound (or active agent) may be mixedwith the solid form of the active agent (or delivery agent compound).The delivery agent compound and the active agent may also be mixed asdry powders. The delivery agent compound and the active agent can alsobe admixed during the manufacturing process.

The dosing solutions may optionally contain additives such as phosphatebuffer salts, citric acid, glycols, or other dispersing agents.Stabilizing additives may be incorporated into the solution, preferablyat a concentration ranging between about 0.1 and 20% (w/v).

The administration compositions may alternately be in the form of asolid, such as a tablet, capsule or particle, such as a powder orsachet. Solid dosage forms may be prepared by mixing the solid form ofthe compound with the solid form of the active agent. Alternately, asolid may be obtained from a solution of compound and active agent bymethods known in the art, such as freeze-drying (lyophilization),precipitation, crystallization and solid dispersion.

The administration compositions of the present invention may alsoinclude one or more enzyme inhibitors. Such enzyme inhibitors include,but are not limited to, compounds such as actinonin or epiactinonin andderivatives thereof. Other enzyme inhibitors include, but are notlimited to, aprotinin (Trasylol) and Bowman-Birk inhibitor.

The amount of active agent used in an administration composition of thepresent invention is an amount effective to accomplish the purpose ofthe particular active agent for the target indication. The amount ofactive agent in the compositions typically is a pharmacologically,biologically, therapeutically, or chemically effective amount. However,the amount can be less than that amount when the composition is used ina dosage unit form because the dosage unit form may contain a pluralityof delivery agent compound/active agent compositions or may contain adivided pharmacologically, biologically, therapeutically, or chemicallyeffective amount. The total effective amount can then be administered incumulative units containing, in total, an effective amount of the activeagent.

The total amount of active agent to be used can be determined by methodsknown to those skilled in the art. However, because the compositions ofthe invention may deliver active agents more efficiently thancompositions containing the active agent alone, lower amounts ofbiologically or chemically active agents than those used in prior dosageunit forms or delivery systems can be administered to the subject, whilestill achieving the same blood levels and/or therapeutic effects.

The presently disclosed delivery agent compounds facilitate the deliveryof biologically and chemically active agents, particularly in oral,intranasal, sublingual, intraduodenal, subcutaneous, buccal,intracolonic, rectal, vaginal, mucosal, pulmonary, transdermal,intradermal, parenteral, intravenous, intramuscular and ocular systems,as well as traversing the blood-brain barrier.

Dosage unit forms can also include any one or combination of excipients,diluents, disintegrants, lubricants, plasticizers, colorants,flavorants, taste-masking agents, sugars, sweeteners, salts, and dosingvehicles, including, but not limited to, water, 1,2-propane diol,ethanol, olive oil, or any combination thereof.

The compounds and compositions of the subject invention are useful foradministering biologically or chemically active agents to any animals,including but not limited to birds such as chickens; mammals, such asrodents, cows, pigs, dogs, cats, primates, and particularly humans; andinsects.

The system is particularly advantageous for delivering chemically orbiologically active agents that would otherwise be destroyed or renderedless effective by conditions encountered before the active agent reachesits target zone (i.e. the area in which the active agent of the deliverycomposition is to be released) and within the body of the animal towhich they are administered. Particularly, the compounds andcompositions of the present invention are useful for orallyadministering active agents, especially those that are not ordinarilyorally deliverable, or those for which improved delivery is desired.

The compositions comprising the compounds and active agents have utilityin the delivery of active agents to selected biological systems and inan increased or improved bioavailability of the active agent compared toadministration of the active agent without the delivery agent. Deliverycan be improved by delivering more active agent over a period of time,or in delivering the active agent in a particular time period (such asto effect quicker or delayed delivery), or in delivering the activeagent at a specific time, or over a period of time (such as sustaineddelivery).

Another embodiment of the present invention is a method for thetreatment or prevention of a disease or for achieving a desiredphysiological effect, such as those listed in the table below, in ananimal by administering the composition of the present invention.Preferably, an effective amount of the composition for the treatment orprevention of the desired disease or for achieving the desiredphysiological effect is administered. Specific indications for activeagents can be found in the Physicians' Desk Reference (54^(th) Ed.,2000, Medical Economics Company, Inc., Montvale, N.J.), which is hereinincorporated by reference. The active agents in the table below includetheir analogs, fragments, mimetics, and polyethylene glycol-modifiedderivatives.

Active Agent Disease and Physiological Effect Growth hormones (includinghuman Growth disorders recombinant growth hormone and growth-hormonereleasing factors and its analogs) Interferons, including α, β and γ.Viral infection, including chronic cancer and multiple sclerosisInterleukin-1; interleukin-2. Viral infection; cancer Insulin;Insulin-like growth factor Diabetes IGF-1. Heparin Thrombosis;prevention of blood coagulation Calcitonin. Osteoporosis; diseases ofthe bone Erythropoietin Anemia Atrial naturetic factor VasodilationAntigens Infection Monoclonal antibodies To prevent graft rejection;cancer Somatostatin Bleeding ulcer; erosive gastritis Proteaseinhibitors AIDS Adrenocorticotropin High cholesterol (to lowercholesterol) Gonadotropin releasing hormone Ovulatory disfunction (tostimulate ovulation) Oxytocin Labor disfunction (to stimulatecontractions) Leutinizing-hormone-releasing- Regulate reproductivefunction hormone; follicle stimulating hormone GlucocerebrosidaseGaucher disease (to metabolize lipoprotein) ThrombopoietinThrombocytopenia Filgrastim Reduce infection in chemotherapy patientsProstaglandins Hypertension Cyclosporin Transplant rejection VasopressinBed-wetting; antidiuretic Cromolyn sodium; Vancomycin Asthma; allergiesDesferrioxamine (DFO) Iron overload Parathyroid hormone (PTH),Osteoporosis; including its fragments. Diseases of the boneAntimicrobials Infection including gram-positive bacterial infectionVitamins Vitamin deficiencies Bisphosphonates Osteoporosis; Paget'sdisease; Inhibits osteoclasts BIBN4096BS-(1- Anti-migraine; calcitoningene- Piperidinecarboxamide. N-[2-[[5- related peptide antagonistamino-1-[[4-(4-pyridinyl)-1- piperazinyl)carbonyl]pentyl]amino]-1-[(3,5-dibromo-4- hydroxyphenyl)methyl]-2-oxoethyl]-4(1,4-dihydro-2-oxo-3(2H0- quinazolinyl)-.[R-(R*,S*)]-)

For example, one embodiment of the present invention is a method fortreating a patient suffering from or susceptible to diabetes byadministering insulin and at least one of the delivery agent compoundsof the present invention.

Following administration, the active agent present in the composition ordosage unit form is taken up into the circulation. The bioavailabilityof the agent can be readily assessed by measuring a knownpharmacological activity in blood, e.g. an increase in blood clottingtime caused by heparin, or a decrease in circulating calcium levelscaused by calcitonin. Alternately, the circulating levels of the activeagent itself can be measured directly.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples illustrate the invention without limitation. Allparts are given by weight unless otherwise indicated.

Proton nuclear magnetic resonance (¹H NMR) analyses for the compoundslisted below were conducted on a 300 MHz Bruker spectrometer usingdimethyl sulfoxide (DMSO-d₆) as the solvent unless otherwise indicated.

Liquid chromatograph/mass spectrometry (LC-MS) analyses were performedwith an Agilent Technologies, LC/MSD 1100 (single quad) having thefollowing parameters:

-   -   Mobile Phase A: 50:950:5 acetonitrile:water:acetic acid (v/v/v)    -   Mobile Phase B: 950:50:5 acetonitrile:water:acetic acid (v/v/v)    -   Gradient Elution: 4 minute linear gradient 0-100% B; total time        per injection is 11 minutes    -   Injection volume: 5 uL    -   Column: ZORBAX Rapid Resolution Cartridge, SB-C18, 2.1×30 mm,        3.5 um    -   Particle size, catalog # 873700-902    -   Column temp: 40° C.    -   UV detection at 244 nm    -   MSD parameters:        -   Source: API-ES, positive polarity        -   Scan Parameters:            -   Mass Range: 125.00-600.00            -   Fragmentor: 60 V            -   Gain: 1.0 EMV            -   Threshold: 150        -   Spray Chamber:            -   Gas Temp. 350 deg. D            -   Drying Gas: 12.0 l/min            -   Neb. Pressure; 40 psig            -   VCap 4000V positive/negative.

EXAMPLE 1 Preparation of Compounds

1a: Preparation of Citrate Salt of Compound 1:

(4-(8-(2-hydroxyphenoxy)octyl)morpholine)citrate

A solution of 27.5 ml (31.4 grams, 157 mmol) of 2-benzyloxyphenyl, 80.0ml (118.82 grams, 434 mmol) of 1,8-dibromooctane and 100 ml of ethanolwas treated with 23.18 grams (168 mmol) of potassium carbonate andheated to reflux for 5.5 hours. The cooled reaction mixture was stirredfor 20 hours at 25° C., filtered and concentrated. The residue wasdiluted with 100 ml of 2:1 hexanes/ethyl acetate and decolorized withcharcoal. The solution was concentrated. This residue was purified byKugelrohr distillation to remove the excess dibromide at 98° C. and 0.5mm of pressure.

The 59.0 grams (151 mmol) of bromide isolated above was dissolved in 100ml of tetrahydrofuran and treated with 28.0 ml (28.0 g, 321 mmol) ofmorpholine. This solution was heated to reflux for 4.5 hours. Theresulting slurry was cooled to 25° C., stirred at 25° C. for 20 hoursand treated with 80 ml of 2N aqueous sodium hydroxide. This mixture wasdiluted with 80 ml of 2:1 hexanes/ethyl acetate. The layers wereseparated. The organic phase was washed with water (3×30 ml) and brine(1×30 ml), dried over sodium sulfate, decolorized with charcoal andconcentrated.

The 59.9 grams of benzyl ether isolated above was dissolved in 80 ml ofethanol and 20 ml of ethyl acetate, treated with 0.55 grams of 10%palladium on charcoal and placed under 58 psig of hydrogen in a Parrshaker. Approximately 20 psig of hydrogen was used up over 20 hours. Thecatalyst was removed by filtration through a Celite pad. The filtratewas concentrated and placed under vacuum over 20 hours.

The 4-8-(2-hydroxyphenoxy) octylmorpholine (37.63 grams, 122.4 mmol,about 80% pure by NMR) isolated above was dissolved in 50 ml of tolueneand added to a warm solution of 21.17 g of citric acid and ethanol.Another 30 ml of toluene was added. The solution was placed in a −4° C.freezer. The solid that formed was isolated by filtration to give 42.9 gof 4-8-(2-hydroxyphenoxy) octylmorpholium citrate, mp 84-6° C. KarlFisher: 0.55% water; Combustion analysis (with water): % C: 57.39(calc'd), 57.63 (found); % H: 7.49 (calc'd), 7.55 (found); % N: 2.79(calc'd), 2.64 (found); 1H NMR Analysis: (d6-DMSO): δ 8.4, bs, 5H; δ6.9, dd, 1H; δ 6.7, m, 3H; δ 3.9, t, 2H; δ 3.7, t, 4H; δ 2.8, bt, 4H; δ2.7, t, 2H; δ 2.6, q, 4H; δ 1.7, p, 2H; δ 1.5, p, 2H; δ 1.4, p, 2H; δ1.3, m, 6H.

1b: Preparation of Mesylate Salt of Compound 1:

(4-(8-(2-hydroxyphenoxy)octyl)morpholine)mesylate

The N-8-(2-hydroxyphenoxy)octylmorpholine (13.3 g, 43.3 mmol, about 80%pure by NMR) isolated above was dissolved in 40 ml of tetrahydrofuranand treated with 2.30 ml (3.41 g, 35.4 mmol) of methanesulfonic acid. Asolid immediately developed and was isolated by filtration to give 8.02g of compound 1 as the mesyalte salt, mp 137-9 C. Combustion analysis: %C: 56.55 (calc'd), 56.50 (found); % H: 8.24 (calc'd), 8.23 (found); % N:3.47 (calc'd), 3.39 (found); % S: 7.94 (calc'd), 7.79 (found); 1H NMRAnalysis: (d6-DMSO): δ 9.6, bs, 1H; δ 8.8, bs, 1H; δ 6.9, dd, 1H; δ 6.7,m, 3H; δ 3.9, t, 4H; δ 3.7, t, 2H; δ 3.4, t, 2H; δ 3.0, bt, 4H; δ 2.4,s, 3H; δ 1.7, m, 4H; δ 1.4, p, 2H; δ 1.3, m, 6H.

1c. Preparation of Compound 3:

7-(4-(2hydroxyphenoxy) heptylmorpholinium citrate

May be made in the same manner as compound 1 using 1,7-dibromohexane asthe alkylating agent. 2.25 g of compound 3 was isolated, mp 120-3 C.Combustion analysis: % C: 56.90 (calc'd), 56.92 (found); % H: 7.27(calc'd), 7.24 (found); % N: 2.88 (calc'd), 2.61 (found); 1H NMRAnalysis: (d6-DMSO): δ 8.6, bs, 5H; δ 6.9, dd, 1H; δ 6.7, m, 3H; δ 3.9,t, 2H; δ 3.7, t, 4H; δ 2.8, bt, 4H; δ 2.7, t, 2H; δ 2.6, q, 4H; δ 1.7,p, 2H; δ 1.5, p, 2H; δ 1.2-1.4, m, 6H.

1d: Preparation of Citrate Salt of Compound 2:

8-(2-hydroxyphenoxy) octyldiethanolamine) citrate

A solution of 27.5 ml (31.4 g, 157 mmol) of 2-benzyloxyphenyl, 80.0 ml(118.82 g, 434 mmol) of 1,8-dibromooctane and 100 ml of ethanol wastreated with 23.18 g (168 mmol) of potassium carbonate and heated toreflux for 5.5 hours. The cooled reaction mixture was stirred for 20hours at 25° C., filtered and concentrated. The residue was diluted with100 ml of 2:1 hexanes/ethyl acetate and decolorized with charcoal. Thesolution was concentrated. This residue was purified by Kugelrohrdistillation to remove the excess dibromide at 980 C and 0.5 mm ofpressure.

The bromide isolated above (4.32 g, 11.0 mmol) and 2.80 ml (3.07 g, 29.2mmol) of diethanolamine were dissolved in 30 ml of tetrahydrofuran andtreated with 5 mL of triethylamine. This solution was heated to refluxfor 3 days. The resulting slurry was cooled to 25° C., stirred at 25° C.for 20 hours and treated with 20 ml of 2N aqueous sodium hydroxide. Thismixture was diluted with 20 ml of ethyl acetate. The layers wereseparated. The organic phase was washed with water (3×30 ml) and brine(1×30 ml), dried over sodium sulfate, and concentrated.

The 3.98 g of benzyl ether isolated above was dissolved in 20 ml ofethanol and 20 ml of ethyl acetate, treated with 0.22 g of 10% palladiumon charcoal and placed under 58 psig of hydrogen in a Parr shaker.Approximately 20 psig of hydrogen was used up over 20 hours. Thecatalyst was removed by filtration through a Celite pad. The filtratewas concentrated and placed under vacuum over 20 hours.

The 8-(2-hydroxyphenoxy)octyldiethanolamine (3.06 g, 9.40 mmol) isolatedabove was dissolved in 10 ml of methyl t-butyl ether and 2 ml ethanol.This solution was added to a warm solution of 1.82 g of citric acid and8 ml ethanol. Another 5 ml of methyl t-butyl ether was added. Thesolution was placed in a −4° C. freezer. The solid that formed wasisolated by filtration to give 2.16 g of 8-(2-hydroxyphenoxy)octyldiethanolammonium citrate, mp<25° C. Karl Fisher: 0.1.71% water;Combustion analysis (with water): % C: 54.74 (calc'd), 55.28 (found); %H: 7.66 (calc'd), 8.16 (found); % N: 2.66 (calc'd), 2.54 (found).

1e: Preparation of Citrate Salt of Compound 4:

4-(6-(4-hydroxyphenoxy)hexyl)morpholine)citrate

A solution of 9.97 g (49.8 mmol) of 4-benzyloxyphenyl, 22.2 ml (34.9 g,143 mmol) of 1,6-dibromohexane and 100 ml of ethanol was treated with7.67 g (55.5 mmol) of potassium carbonate and heated to reflux for 5.5hours. The reaction mixture was cooled to 25° C. At 25° C. thesolidified reaction mixture was diluted with ethyl acetate and ethanol,filtered, and rinsed with copious amounts of ethyl acetate. The filtratewas collected and concentrated to form a solid. The solid was isolatedby filtration.

The 4.20 g (11.6 mmol) of bromide isolated above was dissolved in 30 mlof tetrahydrofuran and treated with 2.20 ml (2.20 g, 25.3 mmol) ofmorpholine. This solution was heated to reflux for 4.5 hours. Theresulting slurry was cooled to 25° C., stirred at 25°C. for 20 hours andtreated with 20 ml of 2N aqueous sodium hydroxide. This mixture wasdiluted with 20 ml of 2:1 hexanes/ethyl acetate. The layers wereseparated. The organic phase was washed with water (3×30 ml) and brine(1×30 ml), dried over sodium sulfate, decolorized with charcoal andconcentrated.

The 4.27 g of benzyl ether isolated above was dissolved in 25 ml ofethanol and 20 ml of ethyl acetate, treated with 0.32 g of 10% palladiumon charcoal and placed under 58 psig of hydrogen in a Parr shaker.Approximately 20 psig of hydrogen was used up over 20 hours. Thecatalyst was removed by filtration through a Celite pad. The filtratewas concentrated and placed under vacuum for over 20 hours.

The 4-6-(4-hydroxyphenoxy) hexylmorpholine (3.05 g, 10.9 mmol) isolatedabove was dissolved in 60 ml of ethanol, 20 ml of ethyl acetate and 20ml of acetone with heating. This solution was added to a warm solutionof 2.10 g of citric acid and ethanol. The mixture was diluted with 50 mlof methyl t-butyl ether and placed in a −4° C. freezer. The solid thatformed was isolated by filtration to give 2.16 g of4-6-(4-hydroxyphenoxy) hexylmorpholinium citrate, mp 125-7° C. KarlFisher: 0.45% water; Combustion analysis (with water): % C: 55.79(calc'd), 55.47 (found); % H: 7.07 (calc'd), 7.03 (found); % N: 2.96(calc'd), 2.92 (found).

1f. Preparation of Citrate Salt of Compound 5:

4-(6-(2-hydroxyphenoxy)hexyl)morpholinium citrate

Preparation is the same as for compound 1 citrate except1,6-dibromohexane was used as the alkylating agent. 10.11 g of compound5 was isolated, mp 76-80 C. Combustion analysis: % C: 55.70 (calc'd),56.11 (found); % H: 7.08 (calc'd), 7.22 (found); % N: 2.95 (calc'd),2.86 (found); 1H NMR Analysis: (d6-DMSO): δ 8.6, bs, 5H; δ 6.9, dd, 1H;δ 6.7, m, 3H; δ 3.9, t, 2H; δ 3.7, t, 4H; δ 2.8, bt, 4H; δ 2.7, t, 2H; δ2.6, q, 4H; δ 1.7, p, 2H; δ 1.5, p, 2H; δ 1.4, p, 2H; δ 1.3, p, 2H.

1 g. Preparation of Compound 6:

8-(4-hydroxyphenoxy)octanamine

A mixture of 4-benzyloxyphenyl (10.23 grams, 51.2 mmol) and ethyl8-bromooctanoate (12.80 grams, 51.0 mmol) in 200 ml of 2-butanone wastreated with 13.8 grams of potassium carbonate (100 mmol) and heated toreflux for 16 hours. The cooled reaction mixture was filtered. Thefiltrate was combined with 100 ml of ethyl acetate and washed insequence with 2N NaOH, water, 1N HCl and brine, dried over anhydroussodium sulfate. Solvent was removed by rotary evaporator to give a whitesolid as the product.

The 18.53 grams (50.1 mmol) of the ester obtained above was dissolved in200 ml of anhydrous tetrahydrofuran. Lithium aluminum hydride (1.9grams, 50 mmol) was added slowly through a powder funnel. This mixturewas stirred at room temperature for 2 hours before cooled in an icebath. Water (2 ml) was added slowly followed by 6 ml of 15% NaOH andthen another 2 ml of water. The mixture was stirred overnight beforefiltration. The filtrate was concentrated to give 16.3 grams of product.

The 16.3 grams (49.7 mmol) of alcohol obtained above was dissolved in amixture of 200 ml of methylene chloride and 10 ml ofN,N-dimethylacetamide. Triethylamine (7.30 grams, 72.3 mmol) was added.The resulting mixture was cooled in an ice-bath before methanesulfonylchloride (7.39 grams, 64.5 mmol) was added. The mixture was then warmedto room temperature and stirred for 20 hours. The mixture was thenwashed in sequence with water, 1N HCl, water, saturated sodiumbicarbonate, water and brine, dried over sodium sulfate. Evaporation ofthe solvent afforded 21.25 grams of product.

The mesylate (20.50 grams, 50.5 mmol) obtained above was dissolved in100 ml of N,N-dimethylacetamide and treated with sodium azide (5.01grams, 77.1 mmol). The mixture was heated at 120° C. for three hoursbefore cooled to room temperature. The mixture was then poured into 200ml water, and the large amount of the solid formed was collected byvacuum filtration (17.25 grams).

The azide (16.64 grams, 47.1 mmol) obtained above was dissolved in 200isopropanol and treated with ammonium formate (11.87 grams, 188.4 mmol).The mixture was heated to 60° C. before palladium on carbon (10% inweight, 1.0 grams) was added slowly through a powder funnel. Thereaction was stirred at 60° C. for one hour before cooled to roomtemperature. Solvent was removed by rotary evaporation to obtain 13.09grams of solids. The solid was recrystallized from ethanol-water toafford 8.90 grams of pure product of 8-(4-hydroxyphenoxy)octanamine, mp115-7° C. % C: 70.85 (calc'd), 70.53 (found); % H: 9.77 (calc'd), 9.92(found); % N: 5.90 (calc'd), 5.67 (found); 1H NMR Analysis: (d6-DMSO): δ6.7, AB, 4H; δ 3.8, t, 2H; δ 3.5, bt, 3H; δ 2.5, t, 2H; δ 1.6, p, 2H; δ1.3, br, 10H.

1 h. Preparation of Citrate Salt of Compound 7:

4-(4-(2-hydroxyphenoxy)butyl)morpholinium Citrate

Preparation is the same as the compound 1 citrate except used1,4-dibromobutane as the alkylating agent. 6.32 g of compound 7 wasisolated, mp 97-9 C. Combustion analysis: % C: 54.17 (calc'd), 54.11(found); % H: 6.59 (calc'd), 6.61 (found); % N: 3.16 (calc'd), 3.08(found); 1H NMR Analysis: (d6-DMSO): δ 6.9, dd, 1H; δ 6.7, m, 3H; δ 4.0,t, 2H; δ 3.7, t, 4H; δ 2.8, bt, 4H; δ 2.7, t, 2H; δ 2.6, q, 4H; δ 1.7,m, 4H.

1i: Preparation of Hydrochloride Salt of Compound 8:

6-(2-acetylphenoxy)-1-dimethylaminohexane hydrochloride

A solution of 9.32 g (68.5 mmol) of 2-hydroxyacetophenone, 11.3 mL (9.94g, 68.5 mmol) of 6-dimethylamino-1-hexanol, and 18.00 g (68.6 mmol) oftriphenylphosphine in 70 mL of tetrahydrofuran (THF) was prepared. Asolution of 13.5 mL (13.86 g, 68.6 mmol) of diisopropyl azodicarboxylate(DIAD) in 30 mL of THF was added to the above solution overapproximately 30 minutes. The reaction mixture was stirred at ambienttemperature for 20 hours, diluted with 100 mL of ethyl acetate andextracted with five 50 mL portions of 1% aqueous hydrochloric acid andtwo 30 mL portions of 10% aqueous hydrochloric acid. The combinedaqueous extracts were brought to pH=9.5 by the addition of 10 N sodiumhydroxide, and extracted with three 50 mL portions of ethyl acetate. Thecombined organic phase was dried over sodium sulfate and concentrated invacuo. The resulting slurry was diluted with 10 mL of ethyl acetate andthe solids removed by filtration through glass wool. The organic phasewas concentrated in vacuo and refrigerated. The resulting solids werediluted with approximately 40 mL of 10% aqueous hydrochloric acid, andthe insoluble fraction removed by filtration. The solution was broughtto pH=9 with 1 N sodium hydroxide, washed with four 30 mL portions ofethyl acetate and one 30 mL portion of water, dried over sodium sulfate,concentrated in vacuo, and stored at −5° C. The resulting solids werestirred in hexanes, and the insoluble fraction removed by filtration.Gaseous hydrochloric acid was bubbled through the filtrate. The hexaneswere decanted off the resulting solids, and the solids were stirred inethyl acetate for approximately 20 hours. These solids were collected byfiltration to give 5.77 g (28.1%) of6-(2-acetylphenoxy)-1-dimethylaminohexane hydrochloride as a pale yellowpowder. Melting point 138-141° C. Combustion analysis: % C: 64.09(calc'd), 63.80 (found); % H: 8.74 (calc'd), 8.60 (found); % N: 4.67(calc'd), 4.76 (found); % Cl: 11.82 (calc'd), 11.63 (found). 1H NMRAnalysis (d6-DMSO): δ 10.8, bs, 1H; δ 7.6, dd, 1H; δ 7.5, dt, 1H; δ 7.1,d, 1H; δ 7.0, dt, 1H; δ 4.1, t, 2H; δ 3.0, m, 2H; δ 2.7, d, 6H; δ 2.5,s, 3H; δ 1.8, m, 2H; δ 1.7, m, 2H; δ 1.5, m, 2H, δ 1.4, m, 2H.

1j. Preparation of Compound 9

The 7-bromoheptyl 2-benzyloxyphenyl ether may be prepared in the samemanner as above from 2-benzyloxyphenyl and 1,7-dibromoheptane. Asuspension of 16.49 g (149.7 mmol) of 2-isopropylimidazole, 28.80 g(76.33 mmol) of 7-bromoheptyl 2-benzyloxyphenyl, 11.2 ml oftriethylamine and 150 ml of dioxane was heated to 80C, causing all thesolids to go into solution. After stirring for 5 hr, the reactionmixture was cooled to 25C, diluted with 50 n ml of methyl t-butyl etherand filtered. The filtrate was diluted with 2:1 methyl t-butyl ether andhexanes and washed with water (3×60 mL) and brine (1×40 mL). The organicphase (the top one) was dried over sodium sulfate concentrated.

The crude 31.0 g of benzyl ether isolated above was dissolved in ethanoland cooled to −4C. The solid that formed was isolated and discarded. Thefiltrate was concentrated to half the volume (150 mL), treated with 0.50g of 10% palladium on charcoal and placed under 53 psig of hydrogen in aParr shaker. Approximately 4 psig of hydrogen was used up over 40 hours.The catalyst was removed by filtration through a Celite pad. Thefiltrate was concentrated. After 2 days, a solid formed, was taken up intoluene, filtered off and recrystallized from ethanol/toluene. Thissolid was subjected to Kugelrohr distillation to remove the2-isopropylimidazole impurity at 66C and 0.1 mm. Upon cooling 5.89 g of(2-hydroxyphenoxy)-heptyl-2-isoproylaimidazole was isolated, mp 93-4C.Karl Fisher: 1.66% water; Combustion analysis (with water): %C: 70.92(calc'd), 70.20 (found); %H: 8.96 (calc'd), 8.80 (found); % N: 8.71(calc'd), 8.52 (found); MS (M+1) 317; 1H NMR Analysis: (d6-DMSO): δ 8.8,bs, 1H; b 7.05, d, 1H; δ 6.9, dd, 1H; δ 6.8, d, 1H; δ 6.7, m, 3H; δ 3.9,m, 4H; δ 3.05, hept, 1H; δ 1.7, m, 4H; δ 1.3-1.5, m, 6H; δ 1.2, d, 6H.

1 k. Preparation of Compound 10

The compound may be made by the same procedure as for compound 9 using1,6-dibromohexane as the alkylating agent and 2-methyl-imidazole. Atotal of 2.11 g of compound 10 was isolated, mp 103-4C. Combustionanalysis: %C: 70.04 (calc'd), 70.24 (found); %H: 8.08 (calc'd), 8.29(found); %N: 10.21 (calc'd), 9.97 (found); 1H NMR Analysis: (d6-DMSO): δ8.8, bs, 1H; δ 7.0, d, 1H; δ 6.9, dd, 1H; δ 6.8, m, 3H; δ 6.7, d, 1H; δ3.9, t, 2H; δ 3.85, t, 2H; δ 1.7, m, 4H; δ1.45, p, 2H; δ 1.3, p, 2H.

1l. Preparation of Compound 11

A solution of 10.0 g (47.8 mmol) of 8-bromo-1-octanol, 10.41 g (120mmol) of morpholine and tetrahydrofuran was heated to reflux for 3 hr.The cooled reaction mixture was treated with saturated aqueous sodiumbicarbonate and extracted with ethyl acetate. The organic phase waswashed with brine, dried over magnesium sulfate and concentrated to give10.50 g of 4-(8-hydroxyoctyl)morpholine.

The crude 4-(8-hydroxyoctyl)-morpholine (2.0 g, 9.3 mmol) was dissolvedin methylene chloride and treated with 10 ml of triethylamine (7.3 g, 72mmol). After cooling in an ice bath, the mixture was treated with 1.28 g(11.2 mmol) of methanesulfonyl chloride stirring for 1 hr before warmingto 25C. After stirring for 2 hour, the reaction mixture was diluted withaqueous sodium bicarbonate solution and extracted with ethyl acetate.The organic phase was washed with brine, dried over magnesium sulfateand concentrated to give 2.4 g of crude mesylate.

A solution of 2.40 g (8.2 mmol) of crude 8-morpholinooctyl mesylate,1.82 g (9.8 mmol) of 2-hydroxy-5-chloro-4-methylacetophenone and 30 mlof dimethylformamide was treated with 2.26 g (16.4 mmol) of potassiumcarbonate and 0.62 g (4.1 mmol) of sodium iodide. The reaction mixturewas heated. After workup and treatment with 1.0 M hydrogen chloride inethyl ether, 2.67 g of5-chloro-4-methyl-2-(8-morpholin-4-yloctyloxy)acetophenonehydro-chloride was isolated, mp 75-6C. Karl Fisher: 4.89% water;Combustion analysis: %C: 57.34 (calc'd), 56.42 (found); %H: 8.11(calc'd), 8.3 (found); %N: 3.18 (calc'd), 3.81 (found); %Cl: 16.12(calc'd), 16.72 (found); 1H NMR Analysis: (d6-DMSO): δ 11.0, bs, 1H; δ7.55, s, 1H; δ 7.2, s, 1H; δ 4.1, t, 2H; δ 3.9, m, 2H; δ 3.8, t, 2H; δ3.0, m, 4H; δ2.5, s, 3H; δ 2.5, m, 2H; δ 2.4, s, 3H; δ 1.8, p, 2H; δ1.7, m, 2H; δ 1.45, m, 2H; δ 1.3, m, 6H.

EXAMPLE 2

2A: Insulin—Oral Delivery

Oral dosing (PO) compositions of delivery agent compound and human zincinsulin (minimum 26 IU/mg available from Calbiochem-Novabiochem Corp, LaJolla, Calif.) were prepared in deionized water. Typically, 500 mg ofdelivery agent compound was added to 1.5 ml of water. The solution wasvortexed, then heated (about 37° C.) and sonicated. The pH was adjustedto about 7 to 8.5 with NaOH or HCl. Additional NaOH was added, ifnecessary, to achieve uniform solubility, and the pH re-adjusted toabout 7 to 8.5. Water was then added to bring the total volume to about2.4 ml and vortexed. About 1.25 mg insulin from an insulin stocksolution (15 mg/ml made from 0.5409 g insulin and 18 ml deionized water,adjusting with HCl and NaOH to pH 8.15 and to obtain a clear solutionusing 40 ml concentrated HCl, 25 ml 10N NaOH and 50 ml 1N NaOH) wasadded to the solution and mixed by inverting. The solution may be usedin the dosing protocol immediately, or alternatively, the solution maybe placed into a 37° C. water bath for one hour prior to dosing. Thefinal delivery agent compound dose, insulin dose and dose volume amountsare listed below in Table 1.

The typical dosing and sampling protocols were as follows. MaleSprague-Dawley rats weighing between about 200-250 g were fasted for 24hours and administered ketamine (44 mg/kg) and chlorpromazine (1.5mg/kg) 15 minutes prior to dosing and again as needed to maintainanesthesia. A dosing group of five animals was administered one of thedosing solutions. For oral dosing, an 11 cm Rusch 8 French catheter wasadapted to a 1 ml syringe with a pipette tip. The syringe was filledwith dosing solution by drawing the solution through the catheter, whichwas then wiped dry. The catheter was placed down the esophagus leaving 1cm of tubing past the incisors. The dosing solution was administered bypressing the syringe plunger.

Blood samples were collected serially from the tail artery, typically attime=15, 30, 60, 120 and 180 minutes. The percent change in glucoselevels from baseline is reported in Table 1.

TABLE 1 Insulin - Oral Delivery Delivery Agent Delivery Compound InsulinVolume Glucose Levels in Agent Dose Dose dose Serum (% change fromCompound (mg/kg) (mg/kg) (ml/kg) baseline ± SD) 1 200 0.5 2   0.3 ± 8.21 200 0.5 2 −5.9 ± 4.6 2 200 0.5 2 −10.8 ± 6.8  3 200 0.5 2 −9.8 ± 4   4200 0.5 2  −2.3 ± 10.6 6 200 0.5 2    6.4 ± 17.1 7 200 0.5 2 −11.7 ±3.4  8 200 0.5 2 −8.2 ± 9.5

The aforementioned procedure was repeated with the followingmodifications:

Male Sprague-Dawley rats weighing from 250 to 300 g were used ratherthan rats weighing between 200 and 250 g. All animals were stored inwire cages. All animals were placed in the room in which the experimentwas performed at least 30 minutes before the experiment. All loud noisesand voices were avoided to reduce stress to the animals.

Test strips used to determine the level of glucose in blood samples wereonly exposed to light as needed. All test strips were storedindividually in closed vials except during use.

When running a control, the control solution was vigorously shaken, thefirst drop was discarded, the bottle tip was wiped off with a kim wipe,and one drop was applied to a test strip.

Blood samples were taken at t=0, 15, 30, 45, and 60 minutes by theFarmer's Wife Technique. Each rat's tail was cut at tip (about 2 mm ofthe tail). The first drop of blood from the animal's tail was not usedto take a blood glucose reading. A fresh drop of blood from the tip ofeach rat's tail was placed on the tip of a test strip.

After baselines, the animals were orally dosed while fully conscience.No anesthesia was given.

2B: Biotinylated Ribonuclease A (bRNase A) Oral Delivery

Oral gavage (PO) dosing solutions of delivery agent compound and bRNaseA (Sigma (Milwaukee, Wis.): Ribonuclease A Type XII-A from bovinepancreas) in deionized water is prepared by mixing. A solution of thedelivery agent compound is made. The delivery agent compound solution isprepared in phosphate buffer and stirred. If necessary, the pH of themixture is adjusted upwards by the addition of aliquots of NaOH of anappropriate normality until the delivery agent compound is completelydissolved. The final pH of the dissolved delivery agent compound isbetween 7.5 and 9.5. The final dosing solutions are prepared by mixing 9volumes of the delivery agent compound solution with 1 volume of abRNase A stock solution (20 mg bRNase A in phosphate buffered saline(PBS)). Final concentrations are 150 mg/ml delivery agent compound and 2mg/ml bRNase A.

The dosing and sampling protocols are as follows. Male Sprague-Dawleyrats weighing 200-250 g are fasted for 24 hours and administeredketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15 minutes prior todosing and again as needed to maintain anesthesia. A dosing group offive animals is administered one of the dosing solutions in thefollowing manner. An 11 cm Rusch 8 French catheter is adapted to a 1 mlsyringe with a pipette tip. The syringe is filled with dosing solutionby drawing the solution through the catheter, which is then wiped dry.The catheter is placed down the esophagus leaving 1 cm of tubing pastthe incisors. The dosing solution is administered by pressing thesyringe plunger. Blood samples are collected serially from the tailartery at 15, 30, 45, 60 and 90 minutes. Serum bRNase A concentrationsare quantified by a modified immunoassay as described below.

Biotinylation of Ribonuclease A

To label each of the RNase A molecules with one biotin molecule, theratio of the activated biotin is maintained at 3 moles biotin/1 moleRNase A. In a representative biotinylation reaction 500 mg of RNase A isdissolved in 20 ml of 50 mM NaHCO₃, pH 7.6. 57.08 mg of EZ-LinkSulfo-NHS-LC-LC Biotin (Pierce Chemical Company, Rockford, Ill.) isadded to the solution, dissolved and allowed to stand on ice for 2hours. The reaction mix is then dialyzed (10,000 MW cutoff dialysismembrane (Pierce, Rockford, Ill.)) against 4 liters of PBS at 4° C.overnight. The reaction mixture is placed in 4 liters of fresh PBS anddialyzed for an additional 4 hours. The dialyzed bRNase A is removedfrom the dialysis membrane, diluted to a final volume of 25 ml with PBS(final concentration of bRNase A=20 mg/ml), and stored a 4° C.

Assay of Serum Levels of Orally Administered bRNase A

In general 100 μl aliquots of the rat sera collected at the various timepoints are placed in the appropriate wells of a 96 well Reacti-BindStreptavidin Coated Polystyrene Plates (Pierce). After a 2 hourincubation period the plates are washed and then incubated with apolyclonal rabbit anti-RNase A (Chemicon, Pittsburgh, Pa.). Afterwashing, the plates are incubated for 2 hours with a polyclonal goatanti-rabbit IgG (Chemicon, Pittsburgh, Pa.) conjugated to alkalinephosphatase. The plates are washed after the incubation and the amountof initially captured bRNase A is detected by the addition ofpara-nitrophenyl phosphate (a substrate for alkaline phosphatase)(Pierce, Rockford, Ill.). The amount of bRNase A circulating in theoriginal rat sera is quantitated by comparison with a standard curve ofbRNAse A which extends from 1000-0.1 ng/mL in fifteen two-folddilutions. The maximum±standard deviation is given in Table 2 below.

TABLE 2 Oral Delivery of RNAase Delivery Agent Delivery Compound bRNAaseVolume Agent Dose Dose dose Mean Peak Compound (mg/kg) (mg/kg) (ml/kg)Serum ng/ml2c: Oral Delivery of BIBN4096BS

Oral gavage (PO) dosing solutions of delivery agent compound and thecalcitonin gene-related peptide antagonist, 1-piperidinecarboxamide,N-[2-[[5-amino-1-[[4-(4-pyridinyl)-1-piperazinyl)carbonyl]pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4(1,4-dihydro-2-oxo-3(2H0-quinazolinyl)-.[R—(R*,S*)]- (BIBN4096BS) in water were prepared. Typically, a solutionof the delivery agent compound was prepared in water and stirred. Thefinal dosing solutions were prepared by mixing the delivery agentcompound with a BIBN4096BS stock solution and diluting to the desiredvolume (usually 1.0 mL). If necessary, the pH of the mixture wasadjusted by the addition of aliquots of aqueous hydrochloric acidsolution of an appropriate normality until the final pH of the dissolveddelivery agent compound was below 7.0. The final compound amounts perdose were 25 mg/kg of BIBN4096BS and 200 mg/kg of delivery agentcompound in a total volume of 1 mL/kg.

The typical dosing and sampling protocols were as follows. MaleSprague-Dawley rats weighing between 200-250 g were fasted for 24 hoursand administered ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15minutes prior to dosing. A dosing group of five rats was administeredone of the dosing solutions. For oral gavage (PO) dosing, an 11 cm Rusch8 French catheter was adapted to a 1 mL syringe with a pipette tip. Thesyringe was filled with dosing solution by drawing the solution throughthe catheter, which was then wiped dry. The catheter was placed down theesophagus leaving 1 cm of tubing past the incisors. Solution wasadministered by pressing the syringe plunger. Blood samples werecollected serially from the tail artery, typically at time=0, 15, 30,45, and 60 minutes for oral. Plasma BIBN4096BS concentrations werequantified by using a liquid chromatography/mass spectrometry/massspectrometry assay method using UV detection. The standard range for theassay was 5-2,000 ng/mL. Previous studies indicated baseline values ofabout 10 ng/mL. The maximum is reported below in Table 3.

TABLE 3 Oral BIBN4096BS Delivery Delivery Agent Delivery CompoundBIBN4096BS Volume Agent Dose Dose dose Mean Peak Compound (mg/kg)(mg/kg) (ml/kg) Serum ± sd ng/ml 1 (Citrate) 200 25 1 540 ± 521 1(Citrate) 200 25 1 148 ± 119 1 (Citrate) 200 25 1 117 ± 76  1 (Citrate)200 25 1 277 ± 332 1 (Citrate) 200 25 1 66 ± 7  1 (Citrate) 200 25 1 153± 158 1 (Mesylate) 200 25 1 408 ± 340 1 (Mesylate) 200 25 1 608 ± 552 2200 25 1 428 ± 340 2 200 25 1 352 ± 248 2 200 25 1 416 ± 438 2 200 25 1756 ± 381 3 200 25 1 166 ± 159 3 200 25 1 451 + 156 3 200 25 1 139 ± 1503 200 25 1 131 ± 114 4 200 25 1 70 ± 39 4 200 25 1 59 ± 26 6 200 25 1 35± 32 6 200 25 1 77 ± 35 6 200 25 1 69 ± 61 7 200 25 1 48 ± 49 7 200 25 112 ± 10 8 200 25 1 59 ± 35 8 200 25 1 115 ± 110 8 200 25 1  93 ± 105 8200 25 1 79 ± 322d. Oral Delivery of Daptomycin2d. Daptomycin—Oral/Intracolonic Delivery

Dosing solutions containing a delivery agent compound and daptomycin(Cubist Pharmaceuticals, Cambridge, Mass.) were prepared in 0.9% normalsaline. A solution of the compound was made either with the sodium saltof the compound or by converting the free acid to its sodium salt. Thefree acid of the delivery agent compound was converted to the sodiumsalt with one equivalent of sodium hydroxide. This mixture was vortexedand placed in a sonicator (about 37° C.). The pH was adjusted to about7.0-7.5 with aqueous HCl or NaOH. Additional NaOH was added, ifnecessary, to achieve uniform solubility, and the pH readjusted. Themixture was vortexed to produce a uniform solution, also usingsonication if necessary. The delivery agent compound solution was mixedwith daptomycin from a stock solution (200 mg daptomycin/mL in 0.9%normal saline and the pH adjusted, if necessary, to between 6.0-7.0 withNaOH or HCl). The stock solution was stored frozen (−20° C.) wrapped infoil, then thawed and warmed gradually to about 25° C. before using. Thedelivery agent-daptomycin mixture was vortexed at low speed to produce auniform solution. The pH was adjusted to about 7.0-7.5 with aqueousNaOH. The solution was then diluted with 0.9% normal saline to thedesired volume (usually 2.0 ml) and concentration and stored wrapped infoil before use. The final delivery agent compound and daptomycin doses,and the dose volumes are listed below in Table 4.

The typical dosing and sampling protocols were as follows. MaleSprague-Dawley rats weighing between 200-250 g were fasted for 24 hoursand were anesthetized with ketamine (44 mg/kg) and thorazine (1.5 mg/kg)15 minutes prior to dosing and again as needed to maintain anesthesia. Adosing group of five animals was administered one of the dosingsolutions. For oral gavage (PO) dosing, an 11 cm Rusch 8 French catheterwas adapted to a 1 ml syringe with a pipette tip. The syringe was filledwith dosing solution by drawing the solution through the catheter, whichwas then wiped dry. The catheter was placed down the esophagus leaving 1cm of tubing past the incisors. Solution was administered by pressingthe syringe plunger. For intracolonic (IC) dosing, a 7.5 cm, 8 fr Ruschcatheter was adapted to a 1 ml syringe with a pipette tip. The dosingcatheter was inserted into the colon through the anus until the tube wasno longer visible. The dosing solution was expressed slowly into thecolon by pressing the syringe plunger.

Heparinized rat blood samples were collected via the ventral tailartery, typically at 0.25, 0.5, 0.75, 1.0, 2.0, and 4.0 hours afterdosing, and stored on ice. Blood samples were then spun (centrifuged) at11,500 rpm for 4 minutes at 4° C. to obtain the plasma (supernatant),which was stored at −70° C. The plasma daptomycin concentrations weremeasured by isocratic reversed phase HPLC, keeping samples at 4° C.during analysis. Blank plasma studies show baseline values of zero.

Results from the animals in each group were averaged for each time pointand the highest of these averages (i.e., mean peak daptomycinconcentration, C_(max)) is reported below in Table 4.

TABLE 4 Daptomycin - Oral/Intracolonic Delivery Delivery Delivery RouteAgent Daptomycin Mean plasma Cmax Agent of Compound Dose Volume dose[daptomycin] ± Compound dosing Dose (mg/kg) (mg/kg) (mL/kg) SD, μg/mL 1oral 200 50 2 13.7 ± 5.6  2 oral 200 50 2 15.3 ± 9   3 oral 200 50 211.1 ± 5.9  5 oral 200 50 2 15.76 ± 3.4  5 oral 200 50 2 5.9 ± 1.9 5oral 200 50 2 13.6 ± 7.54 *AUC = Total AUC_(0→∞) **AUC = AUC_(0→4h)2e. Oral Delivery of human Growth Hormone Releasing Factor Analog(trans-3-henxenoyl hGRF NH₂)

Oral dosing (PO) compositions of delivery agent compound and GRF analogg (available from Theratechnologies, Quebec Canada U.S. Pat. Nos.5,861,379 and 6,020,311) were prepared in deionized water. Typically,500 mg of delivery agent compound was added to 1.5 ml of water. The freebase of the delivery agent compound was converted to the salt bystirring the resultant solution and adding one equivalent of hydrogenchloride. The solution was vortexed, then heated (at about 37° C.) andsonicated. The pH was adjusted to about 7 to 8.5 with NaOH or HCl.Additional NaOH or HCl was added, if necessary, to achieve uniformsolubility, and the pH re-adjusted to about 7 to 8.5. Water was thenadded to bring the total volume to about 2.4 ml and vortexed. About 25mg of GRF-Analog stock solution (50 mg/ml made from 100 mg GRF-Analogand 2 ml deionized water, adjusting with HCl to pH 4.0) was added to thesolution and mixed by inverting. The solution was immediately used inthe dosing protocol, or alternatively, the solution was placed into a37° C. water bath for one hour prior to dosing.

The typical dosing and sampling protocols were as follows. MaleSprague-Dawley rats weighing between about 200-250 g were fasted for 24hours and administered ketamine (44 mg/kg) and chlorpromazine (1.5mg/kg) 15 minutes prior to dosing and again as needed to maintainanesthesia. A dosing group of five animals was administered one of thedosing solutions. For oral dosing, an 11 cm Rusch 8 French catheter wasadapted to a 1 ml syringe with a pipette tip. The syringe was filledwith dosing solution by drawing the solution through the catheter, whichwas then wiped dry. The catheter was placed down the esophagus leaving 1cm of tubing past the incisors. The dosing solution was administered bypressing the syringe plunger.

Blood samples were collected serially from the tail artery, typically attime=0, 15, 30, 60, & 120 minutes. Plasma GRF-Analog levels weredetermined by RIA (first antibody Peninsula Labs, RIN 8061; secondantibody Linco Research Labs, 5060-10). Plasma GRF-Analog concentrations(pg/ml) were measured for each time point for each of the five animalsin each dosing group. The five values for each time point were averagedand the results plotted as plasma GRF-analog concentration versus time.The maximum (peak) are reported below in Table 6.

TABLE 5 human Growth Hormone Releasing Factor analog (trans-3-henenoylhGRF NH₂) Delivery Delivery Delivery Route Agent hGRF Volume Mean plasmaAgent of Compound Dose dose Cmax ± Compound dosing Dose (mg/kg) (mg/kg)(mL/kg) SD, μg/mL 1 (Citrate)   oral 200 10 2 194 ± 388 1 (Mesylate)oral 200 10 2 1.21 × 10⁵ ± 1.45 × 10⁵ 1 (Mesylate) oral 200 10 2 1.84 ×10⁴ ± 4544         1 (Mesylate) oral 200 10 2 1.39 × 10⁴ ± 5237        1 (Mesylate) oral 200 10 2 2.69 × 10⁵ ± 1.19 × 10⁴ 2 oral 200 10 2 1.57× 10⁵ ± 1.37 × 10⁵ 2 oral 200 10 2 1.92 × 10⁵ ± 1.66 × 10⁵ 2 oral 200 102 1.46 × 10⁵ ± 1.26 × 10⁵ 3 oral 200 10 2  781 ± 1469 3 oral 200 10 21.43 × 10⁵ ± 1.19 × 10⁵ 3 oral 200 10 2 2.28 × 10⁵ ± 1.09 × 10⁵ 3 oral200 10 2 2.10 × 10⁴ ± 1.53 × 10⁴ 5 oral 200 10 2 22,709 ± 13,067 5 oral200 10 2 1.78 × 10⁴ ± 3.20 × 10⁴ 5 oral 200 10 2 4911 ± 3250 5 oral 20010 2 1.43 × 10⁴ ± 1.39 × 10⁴ 5 oral 200 10 2 8.12 × 10⁴ ± 1.63 × 10⁵ 10 oral 200 10 2 3848 ± 995 2f. Interferon—Oral Delivery

Dosing solutions of delivery agent compound and interferon alfacon-1(IFN) (available as Infergen® from InterMune, Inc. of Brisbane, Calif.)were prepared in deionized water. The free acid of the delivery agentcompound was converted to the sodium salt with one equivalent of sodiumhydroxide. Typically, a solution of the delivery agent compound wasprepared in water and stirred, adding one equivalent of sodium hydroxide(1.0 N) when making the sodium salt. This mixture was vortexed andplaced in a sonicator (about 37° C.). The pH was adjusted to about 7.0to 8.5 with aqueous NaOH. The mixture was vortexed to produce a uniformsuspension or solution, also using sonication and heat if necessary.Additional NaOH was added, if necessary, to achieve uniform solubility,and the pH re-adjusted to about 7.0 to 8.5. The delivery agent compoundsolution was mixed with an IFN stock solution (about 22.0 to 27.5 mg/mlin phosphate buffered saline) and diluting to the desired volume(usually 3.0 ml). The final delivery agent compound and IFN doses, andthe dose volumes are listed below in Table 6.

The typical dosing and sampling protocols were as follows. MaleSprague-Dawley rats weighing between 200-250 g were fasted for 24 hoursand administered ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15minutes prior to dosing and again as needed to maintain anesthesia. Adosing group of five animals was administered one of the dosingsolutions. An 11 cm Rusch 8 French catheter was adapted to a 1 mlsyringe with a pipette tip. The syringe was filled with dosing solutionby drawing the solution through the catheter, which was then wiped dry.The catheter was placed down the esophagus leaving 1 cm of tubing pastthe incisors. The dosing solution was administered by pressing thesyringe plunger.

Blood samples were collected serially from the tail artery, typically attime=0, 15, 30, 45, 60 and 90 minutes. Serum IFN concentrations werequantified using Cytoscreen Immunoassay Kit for human IFN-alpha (catalog# KHC4012 from Biosource International, Camarillo, Calif.). Previousstudies indicated baseline values of about zero. Results from theanimals in each group were averaged for each time point. The maximum ofthese averages (i.e., the mean peak serum IFN concentration) is reportedbelow in Table 6.

TABLE 6 Interferon - Oral Delivery Delivery Agent Delivery Compound IFNVolume Mean Peak Agent Dose Dose dose Serum [IFN] Compound (mg/kg)(mg/kg) (ml/kg) (ng/ml) ± SD 8 200 1 1 0 ± 0

The above mentioned patents, applications, test methods, andpublications are hereby incorporated by reference in their entirety.

Many variations of the present invention will suggest themselves tothose skilled in the art in light of the above detailed description. Allsuch obvious variations are within the fully intended scope of theappended claims.

1. A compound selected from

and salts thereof.
 2. A composition comprising: (A) an active agent; and(B) at least one compound according to claim 1 or a salt thereof.
 3. Thecomposition of claim 2, wherein the active agent is selected from thegroup consisting of a biologically active agent, a chemically activeagent, and a combination thereof.
 4. The composition of claim 3, whereinthe biologically active agent comprises at least one protein,polypeptide, peptide, hormone, polysaccharide, mucopolysaceharide,carbohydrate, or lipid.
 5. The composition of claim 3, wherein thebiologically active agent is selected from the group consisting of:BJBN-4096BS, growth hormones, human growth hormones recombinant humangrowth hormones (rhGH), bovine growth hormones, porcine growth hormones,growth hormone releasing hormones, growth hormone releasing factor,interferons, α-interferon, β-interferon, γ-interferon, interleukin-1,interleukin-2, insulin, porcine insulin, bovine insulin, human insulin,human recombinant insulin, insulin-like growth factor (IGF), IGF-1,heparin, unfractionated heparin, heparinoids, dermatans, chondroitins,low molecular weight heparin, very low molecular weight heparin, ultralow molecular weight heparin, calcitonin, salmon calcitonin, eelcalcitonin, human calcitonin; erythropoietin (EPO), atrial natureticfactor, antigens, monoclonal antibodies, somatostatin, proteaseinhibitors, adrenocorticotropin, gonadotropin releasing hormone,oxytocin, leutinizing-hormone-releasing-hormone, follicle stimulatinghormone, glucocerebrosidase, thrombopoeitin, filgrastim. postaglandins,cyclosporin, vasopressin, cromolyn sodium, sodium chromoglycate,disodium chromoglycate, vancomycin, desferrioxamine (DFO), parathyroidhormone (PTH), fragments of PTH, antimicrobials, anti-fungal agents,vitamins; analogs, fragments, mimetics and polyethylene glycol(PEG)-modified derivatives of these compounds; and any combinationthereof.
 6. The composition of claim 3, wherein the biologically activeagent comprises insulin, BIBN-4096BS, calcitonin, parathyroid hormone,erythropoietin, growth hormones or combinations thereof.
 7. Thecomposition of claim 3, wherein the biologically active agent comprisesBIBN-4096BS.
 8. The composition of claim 3, wherein the biologicallyactive agent comprises insulin.
 9. A dosage unit form comprising: (A)the composition of claim 6; and (B) (a) an excipient, (b) a diluent, (c)a disintegrant, (d) a lubricant, (e) a plasticizer, (f) a colorant, (g)a dosing vehicle, or (h) any combination thereof.
 10. The dosage unitform of claim 9, wherein the active agent is selected from the groupconsisting of a biologically active agent, a chemically active agent,and a combination thereof.
 11. The dosage unit form of claim 10, whereinthe biologically active agent comprises at least one protein,polypeptide, peptide, hormone, polysaccharide, mucopolysaccharide,carbohydrate, or lipid.
 12. The dosage unit form of claim 10, whereinthe biologically active agent is selected from the group consisting of:BIBN-4096BS, growth hormones, human growth hormones (hGH), recombinanthuman growth hormones (rhGH), bovine growth hormones, porcine growthhormones, growth hormone releasing hormones, growth hormone releasingfactor, interferons, α-interferon, β-interferon, γ-interferon,interleukin-1, interleukin-2, insulin, porcine insulin, bovine insulin,human insulin, human recombinant insulin, insulin-like growth factor,insulin-like growth factor-1, heparin, unfractionated heparin,heparinoids, dermatans, chondroitins, low molecular weight heparin, verylow molecular weight heparin, ultra low molecular weight heparin,calcitonin, salmon calcitonin, eel calcitonin, human calcitonin;erythropoietin, atrial naturetic factor, antigens, monoclonalantibodies, somatostatin, protease inhibitors, adrenocorticotropin,gonadotropin releasing hormone, oxytocin,leutinizing-hormone-releasing-hormone, follicle stimulating hormone,glucocerebrosidase, thrombopoeitin, fllgrastim. postaglandins,cyclosporin, vasopressin, cromolyn sodium, sodium chromoglycate,disodium chromoglycate, vancomycin, desferrioxamine, parathyroidhormone, fragments of PTH, antimicrobials, anti-fungal agents, vitamins;analogs, fragments, mimetics and polyethylene glycol-modifiedderivatives of these compounds; and any combination thereof.
 13. Thedosage unit form of claim 10, wherein the biologically active agentcomprises insulin, BJBN-4096BS, calcitonin, parathyroid hormone,erythropoietin, human growth hormones or combinations thereof.
 14. Thedosage unit form of claim 9, wherein the active agent comprisesrecombinant BIBN-4096BS.
 15. The dosage unit form of claim 9, whereinthe active agent comprises insulin.
 16. The dosage unit form of claim 9,wherein the dosage unit form comprises a dosing vehicle comprising atablet, a capsule, a powder, or a liquid.
 17. The dosage unit form ofclaim 9, wherein the dosing vehicle is a liquid selected from the groupconsisting of water, 1,2-propane diol, ethanol, and any combinationthereof.
 18. A method for administering a biologically-active agent toan animal in need of the agent, the method comprising administeringorally to the animal the composition of claim
 3. 19. The composition ofclaim 2, wherein the active agent is a bisphosphonate.
 20. Thecomposition of claim 19, wherein the bisphosphonate is selected fromalendronate, tiludronate, etidronate, clodronate, pamidronate,olpadronate, incadronate, and mixtures thereof.
 21. The compound ofclaim 1, wherein the compound is

or a salt thereof.
 22. The compound of claim 1, wherein the compound is

or a salt thereof.
 23. The compound of claim 1, wherein the compound is

or a salt thereof.
 24. The compound of claim 1, wherein the compound is

or a salt thereof.
 25. The compound of claim 1, wherein the compound is

or a salt thereof.
 26. The compound of claim 1, wherein the compound is

or a salt thereof.
 27. The compound of claim 1, wherein the compound is

or a salt thereof.
 28. The compound of claim 1, wherein the compound is

or a salt thereof.
 29. The composition of claim 5, wherein the compoundin (B) is

or a salt thereof.
 30. The composition of claim 5, wherein the compoundin (B) is

or a salt thereof.
 31. The composition of claim 5, wherein the compoundin (B) is

or a salt thereof.
 32. The composition of claim 5, wherein the compoundin (B) is

or a salt thereof.
 33. The composition of claim 5, wherein the compoundin (B) is

or a salt thereof.
 34. The composition of claim 5, wherein the compoundin (B) is

or a salt thereof.
 35. The composition of claim 5, wherein the compoundin (B) is

or a salt thereof.
 36. The composition of claim 5, wherein the compoundin (B) is

or a salt thereof.
 37. 8-(2-hydroxyphenoxy)octyldiethanolamine or a saltthereof.
 38. 4-(6-(2-hydroxyphenoxy)hexyl)morpholine or a salt thereof.39. A pharmaceutical composition comprising: (A) an active agent; and(B) 8-(2-hydroxyphenoxy)octyldiethanolamine or a salt thereof.
 40. Thepharmaceutical composition of claim 39, wherein the active agent is abisphosphonate.
 41. The composition of claim 40, wherein thebisphosphonate is selected from alendronate, tiludronate, etidronate,clodronate, pamidronate, olpadronate, incadronate, and mixtures thereof.42. The pharmaceutical composition of claim 39, wherein the active agentis erythropoietin.
 43. The pharmaceutical composition of claim 39,wherein the active agent is follicle stimulating hormone.
 44. Apharmaceutical composition comprising: (A) an active agent; and (B)4-(6-(2-hydroxyphenoxy)hexyl)morpholine or a salt thereof.